Generation of endogenous hydrogen sulphide by cystathionine gamma-lyase limits renal ischaemia/reperfusion injury and dysfunction

Pinpat Tripatara1, Nimesh Patel1, Massimo Collino2, Margherita Gallicchio2, Julius Kieswich1, Sara Castiglia2, Elisa Benetti2, Keith Stewart3, Paul Brown3, Mohammed Yaqoob1, Roberto Fantozzi2, Christoph Thiemermann1
1William Harvey Research Institute, Queen Mary - University of London, London, UK,
2University of Turin, Turin, Italy, 3University of Aberdeen, Aberdeen, UK

The generation of hydrogen sulphide by cystathionine gamma-lyase (CSE) may either limit (Sivarajah et al., 2006) or contribute (Qu et al., 2006) to the degree of tissue injury caused by ischaemia/reperfusion. Seventy-four male Wistar rats (200-320 g) were used to investigate the effects of endogenous and exogenous hydrogen sulphide in renal ischaemia/reperfusion injury (IRI). Rats were subjected to 45 min ischaemia and up to 72 h reperfusion. Administration of the irreversible CSE inhibitor, dL-propargylglycine, prevented the recovery of renal function (serum creatinine) following ischaemia and 72 h reperfusion. The hydrogen sulphide donor sodium hydrosulphide attenuated renal, tubular and glomerular dysfunction and renal injury caused by ischaemia and 6 h reperfusion. Western blot analysis of kidneys taken at 30 minutes reperfusion showed that sodium hydrosulphide significantly attenuated phosphorylation of p-38, JUN 1/2, and ERK 1/2, and activation of NF-κB. At 6 h reperfusion, sodium hydrosulphide significantly attenuated acute tubular necrosis (histology), the activation of caspase-3 and Bid, the decline in the expression of anti-apoptotic Bcl-2, and the expression of NF-κB dependent proteins (iNOS, COX-2, and ICAM-1). These findings suggest that (i) the synthesis of endogenous hydrogen sulphide by CSE is essential to protect the kidney against IRI and aids in the recovery of renal function following IRI, (ii) hydrogen sulphide generated by sodium hydrosulphide reduces IRI and morphological changes of the kidney, and (iii) the observed protective effects of hydrogen sulphide are due to both anti-apoptotic and anti-inflammatory effects.

Qu K, et al. (2006). Stroke 37, 889-893; Sivarajah A, et al. (2006). Shock 26, 154-161